Military traumatic brain injury (TBI) has risen markedly in the current wars in Iraq and Afghanistan, and may occur in isolation or as a component of severe battlefield polytrauma. Recently, there have been estimates of 15-20% of warfighters (over 300,000 soldiers) having served in Iraq or Afghanistan having sustained at least mild TBI. These staggering numbers of afflicted warfighters make the chronic effects of TBI one of the most pressing issues affecting our Veterans. Accordingly, the overall objective of this proposal is to identify the mechanism(s) and progressive changes underlying the transition from acute to chronic pathology following closed-head TBI. Our central hypothesis is that a single severe or repeated mild closed-head TBI induces slowly progressive neurodegenerative changes over months to years post-insult. We believe these long-term neurodegenerative changes will be most apparent in the hippocampus, nigrostriatal system, aspects of the cerebral cortex, and diffuse white matter. Moreover, we hypothesize that a driving mechanism for these neurodegenerative changes is the gradual intra-axonal accumulation (and concomitant pre-synaptic depletion) of alpha-synuclein - an amyloidogenic protein - that eventually leads to more widespread axonal dysfunction, loss of synaptic efficacy, and neuronal degeneration. Initially, this will manifest as neurophysiological deficits affecting axonal efficacy and synaptic function, and will underlie a gradual neurobehavioral decline in learning, problem-solving, and motor function. To test these hypotheses, we have assembled a multi-faceted team of investigators with expertise in neurodegenerative pathologies, rodent and porcine models of TBI, and neural systems electrophysiology. We will use a pro-amyloidogenic transgenic mouse model of TBI and a swine model of closed-head rotational acceleration-induced TBI to mechanistically evaluate the pathophysiological progression from 1 month to 2 years post-injury. Importantly, the transgenic mouse studies (expressing human alpha-synuclein) will be used to directly compare the pathophysiology and neurodegenerative mechanisms in blast-TBI versus impact-TBI. In both mice and pigs, we will employ a comprehensive battery of tests including: (1) assessment of evolving neurodegenerative changes including diffuse axonal injury (DAI), Parkinson's-like Lewy pathology, Alzheimer's-like amyloidosis and tauopathies, synaptic loss, and neuroinflammation; (2) neurobehavior testing of learning, memory, motor, and problem solving; and (3) neurophysiological measurements using electrophysiological techniques sensitive to axonal loss/dysfunction, synaptic changes, and excitability changes. The evaluation of TBI-induced chronic neurodegeneration, neurobehavior, and neurophysiology in the same animals is a unique and powerful experimental platform to detect subtle neurological changes, investigate precipitating pathophysiology, and establish specific structure-function relationships. Importantly, these will be evaluated following either a single moderate or severe injury, or following repeated mild injuries. Although there is mounting evidence for links between TBI and early onset of neurodegenerative pathologies, the mechanisms of these progressive neuropathological changes following militarily relevant single or repetitive closed-head TBI are unknown. However, establishing the pathophysiological links is critical for the long-term health and neurological function of our Veterans, and thus underscores the importance and relevance of the current proposal.